Within the central and peripheral nervous systems, neurons conduct nerve impulses by releasing neurotransmitters, chemicals that enable nerve cells to communicate. Acetylcholine (ACh) is a neurotransmitter which transmits nerve impulses in cholinergic neurons. ACh plays a crucial role in learning and memory. Decreased presence of acetylcholine has been found in Parkinson's disease (PD), dementia due to multiple strokes, multiple sclerosis, schizophrenia, and is a major characteristic of Alzheimer's disease (AD). In addition, autopsy studies on patients with AD have revealed lesions in the cholinergic neurons of the nucleus basalis. Thus, the loss of ACh is thought to account for the loss of cognitive functions such as learning and memory that is a characteristic of many forms of dementia, including Alzheimer's disease-related dementia.
N-methyl-D-aspartate (NMDA) receptors are ligand-gated ion channels located primarily within the central nervous system (CNS). They belong to the family of ionotropic glutamate receptors and exist as multiple subtypes due to the different combinations of subunits—NR1, NR2 (NR2A, NR2B, NR2C, NR2D) and NR3—that can be expressed. They exhibit multiple distinct binding sites. Therefore, in addition to the agonist binding site, there are binding sites for various compounds that enhance, modulate and inhibit the activation of the receptor.
NMDA receptors are involved in neuronal communication and play important roles in synaptic plasticity and mechanisms that underlie learning and memory. Under normal conditions, the NMDA receptors engage in synaptic transmission via the neurotransmitter, glutamate. However, abnormally high levels of glutamate (due to a diseased state) lead to over-activation of these receptors resulting in an excess of Ca2+ influx. This results in neuronal damage through the generation of free radicals such as nitric oxide (NO) and reactive oxygen species (ROS), loss of ATP, and loss of mitochondrial membrane potential. Decreased nerve cell function and neuronal cell death eventually occur. Known as excitotoxicity, this process also occurs if the cell's energy metabolism is compromised.
NMDA over-activation is implicated in neurodegenerative diseases and other pathological conditions as it causes neuronal loss and cognitive impairment. In fact, NMDA receptor-mediated excitotoxicity plays a part in the final common pathway leading to neuronal injury in a variety of neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and Huntington's disease, as well as conditions such as stroke and neuropathic pain. In fact, recent findings have implicated NMDA receptors in many more neurological disorders than previously thought such as multiple sclerosis, cerebral palsy (periventricular leukomalacia), and spinal cord injury, as well as in chronic and severe mood disorders (Mathew et al., 2005)
Compounds currently known in the art exhibit either cholinergic activity or NMDA antagonist activity—but not both. A number of tacrine derivatives (bis-tacrines, chloro-substituted bis-tacrines, chloro-substituted tacrines, etc.) have also been developed to treat Alzheimer's disease. While these compounds are reported to be highly potent and selective against AChE, no NMDA antagonist activity has been detected.
Cholinergic compounds exhibiting acetylcholinesterase inhibitory activity are known and available in the market. Donepezil, galantamine and rivastigmine are recognized and readily prescribed cholinergic drugs that have received FDA approval for mild to moderate Alzheimer's disease. While these drugs show slightly different pharmacological properties, they all work by inhibiting the breakdown of acetylcholine. The major difference between these compounds and those of the present invention is that they exert their influence via a single mechanism of action only, i.e. the inhibition of acetylcholinesterase. They are not NMDA receptor antagonists. Thus, their therapeutic purpose is focused primarily on enhancing the cholinergic effect. Furthermore, these compounds are only suitable for early stage dementia in AD.
Due to recent findings of the involvement of NMDA receptors in a variety of neuropathic disease states and conditions, NMDA antagonists as therapeutic drugs have become more commonly researched. One obstacle to the development of NMDA antagonists as neurotherapeutic drugs is that despite their significant neurotherapeutic potential, many promising NMDA antagonists also exhibit psychotogenic and neurotoxic properties. For example, MK-801 (dizocilpine maleate) has been shown to confer a degree of neuroprotection in ischemic stroke. MK-801, however, is also associated with pyschotropic and adverse motor effects. A few NMDA antagonists have been approved for clinical use for a variety of neuro-pathological conditions such as epilepsy and neuropathic pain and neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Memantine is a non-competitive NMDA antagonist recently approved (in 2004) for the treatment of vascular dementia and dementia symptoms in moderate to severe cases of Alzheimer's disease. Memantine is the only compound in this class of compounds that has successfully received FDA-approval for AD. The mechanism of inhibiting glutamate-induced neurotoxicity is similar to that of the novel compounds. However, unlike the novel compounds, memantine does not affect the cholinergic synaptic pathway.
However, recently the known potent AChE inhibitor, bis-9-amino-1,2,3,4-tetrahydroacridine (also known as bis(7)-tacrine), has also been shown to interact with NMDA receptors to reduce glutamate-induced excitotoxicity, a mechanism independent of its AChE inhibitory and cholinergic transmission activities (Li et al, 2005).
Huperzine A, another known potent anti-cholinesterase inhibitor isolated from the Chinese club moss Huperzia serrata, also has the ability to interact with the NMDA receptor in a non-competitive manner (Gordon et al, 2001). Huperzine A can protect against excitotoxicity by blocking NMDA ion channels and unlike MK-801 and other NMDA antagonists, does so in the absence of psychomimetic side-effects. This makes Huperzine A an ideal candidate for treating acute and chronic neuro-related disorders. However, as Huperzine A is derived from a naturally occurring herb, it is not patentable and thereby has little chance of being developed into a therapeutic drug by biopharmaceutical companies.
It is an object of the present invention to provide improved or alternative compounds useful for the treatment or prevention of neurodegenerative disorders.